Amyloid deposition can begin over a decade before the earliest clinical symptoms of Alzheimer's disease (AD) and in vivo amyloid imaging may allow preclinical diagnosis and more precise identification of very early or atypical cases. The development of Pittsburgh Compound B (PIB), the positron emission tomography (PET) amyloid-imaging agent (developed by members of our group), has introduced new possibilities for in vivo assessment of amyloid deposition in man. The primary objective of the R21 research is to develop and evaluate a multimodality functional imaging methodology that performs voxel-level integration of amyloid deposition (PIB retention) and neuropsychological-task-induced brain activation results to yield more comprehensive and sensitive assessments of asymptomatic and pre-clinical subject status. Preliminary data indicate earliest PIB retention in frontal and posterior cingulate/precuneus areas and PIB retention in these areas was associated with performance on cognitive shifting and delayed word recall tasks. Forty subjects will be studied using functional magnetic resonance imaging (fMRI) during the performance of both a cognitive control task and a declarative memory task. Both amyloid negative (PIB-) and amyloid positive (PIB+) control and mild cognitive impairment (MCI) subjects will be studied, as well as PIB+ mild AD subjects. Multivariate statistical analyses will be performed on a voxel basis to relate PIB retention to both regional fMRI task activation and signal covariation among brain areas-of-interest (functional connectivity). It is expected that a multivariate outcome will be determined that is an integrative index of subject status that is more sensitive and informative than the individual regional PIB PET measures, fMRI results, or cognitive test results. Only fMRI studies will be performed as part of the R21 research, as PIB PET data will be available in the same subjects as part of ongoing longitudinal studies (R37 AG025516 and P01 AG025204). The significance of this integrative multimodality imaging approach is that it can be applied at any point to assess amyloid deposition and its functional sequelae for the improved identification of asymptomatic and early AD pathology, to better identify those individuals who could benefit from intervention therapies, facilitate understanding of natural disease progression, and improve diagnostic accuracy. The proposed research will uniquely allow for the development an integrated neuroimaging measure of amyloid deposition and the brain dysfunction related to the amyloid pathology. The significance of this integrative imaging approach is that it can be applied at any point in time to better identify those individuals who could benefit from intervention therapies, facilitate understanding of natural disease progression, and improve diagnostic accuracy. This research has the potential to provide information that has not previously been obtainable and facilitate understanding of the impact of progressive amyloid deposition on both cognitive performance and functional brain circuitry. [unreadable] [unreadable] [unreadable]